Glutamate is an important transmitter in the central nervous system but there has been minimal investigation of the function of glutamate and its receptors in the skin. Recently, however, it has been demonstrated that application of glutamate to isolated rat tail skin elicits nociceptive reflexes in spinal cord ventral roots, indicating that glutamate may serve as a neurotransmitter at the level of the peripheral nerve terminal. Another line of evidence supporting an important role for peripheral glutamate in nociception is our preliminary immunohistochemical data, localizing AMPA, kainate and NMDA receptors in unmyelinated axons in rat glabrous skin. The long-term goal of this project is to elucidate the role of the peripheral glutamate receptors in nociceptive transmission. Once this is defined in normal rats, the contributions of peripheral glutamate and its receptors to sensory abnormalities characterizing an animal model of painful peripheral neuropathy will be investigated. Preliminary data indicate that in this pathophysiological state, activation of peripheral glutamate receptors enhances neuropathic pain, in contrast, blocking these receptors decreases pain behaviors. Thus, our data strongly suggest that glutamate receptor activation in the skin is an important peripheral mechanism which has heretofore been unrecognized as a contributor to sensory abnormalities and pain. The specific aims in this proposal focus on 1) identifying the location of glutamate receptor subtypes on neural elements in the skin; 2) elucidating the role of peripheral glutamate receptors in nociceptive transmission in both normal and neuropathic rats; 3) determining whether primary afferent activity results in an increase in glutamate content in the skin: 4) determining whether sensitization of peripheral axons is a mechanism underlying this phenomenon and 5) determining the role of the sympathetic efferents in glutamate-evoked nociception. Insight into the role of glutamate receptors in the skin of naive and neuropathic rats has many clinical ramifications. Therapy for pathological pain states could conceivable involve glutamate antagonists applied as topical ointments or local injections. Exploiting this peripheral glutamate receptor mechanism may result in improved clinical treatment of pain disorders.